Tumor growth relies on the dysregulation of cancer cell properties associated with an intense host tissue remodeling. Mitogenic signals consist of growth factors acting through cell surface receptors, extracellular matrix (ECM) components and cell-cell adhesion molecules. Several proteases are known to control the bioavailability and activity of growth factors, cytokines and chemokines that target specific receptors regulating cell survival, growth, migration, as well as inflammation and angiogenesis. These effects rely on the release of active molecules from the ECM, the cleavage of growth factors binding proteins or the shedding of receptor ligands from the cell surface. Several protease of the zinc-binding endopeptidase family including matrix metalloproteinases (MMPs) and A Disintegrin and Metalloproteinases (ADAMs) are key regulators of molecules acting at the cell surface. They are able to degrade almost all ECM components as well as other molecules including cytokines and growth factors. For instance, MMP9 and MMP2 are responsible for the release of the Vascular Endothelial Growth Factor (VEGF) from the ECM and the activation of Transforming Growth Factor-beta (TGFβ), whereas ADAM10 and TACE (ADAM17) shed several EGFR ligands from the cell surface such as TGFα, amphiregulin and proHB-EGF.
The membrane insertion of ADAMs and membrane type-MMPs (MT-MMPs) helps these proteases to localize to specific membrane microdomains and reach key membrane and pericellular proteins to confer a unique set of regulatory mechanisms. A growing number of evidences underline a functional crosstalk between cell surface-associated proteases and kinases during cancer progression. MT-MMPs that play a key role in cancer progression and vascular diseases are linked to the cell membrane either through a transmembrane domain (MT1-, MT2-, MT3-, MT5-MMP) or a glycosyl phosphatidyl inositol (GPI) anchor (MT4- and MT6-MMP). The transmembrane MT1-MMP has been reported to induce intracellular signaling through Scr and MAP kinases cascade. In sharp contrast to this well documented MT1-MMP-mediated signaling, a putative outside-in cell signaling through the GPI anchored MT-MMPs (MT4 and MT6-MMPs) is unknown. Although, most MMPs are produced by host cells, MT4-MMP (MMP17) is produced by tumor cells in human breast cancer samples (Chabottaux, V. et al. “Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases”, Cancer Res 66, 5165-5172 (2006)). MT4-MMP emerged recently as a key intrinsic feature of breast cancer cells that stimulates tumor growth and metastasis into the lung, but into to lymph nodes (Chabottaux, V. et al., Cancer Res 66, 5165-5172 (2006); Chabottaux, V., et al., J Cell Mol Med 13, 4002-4013 (2009); Host, L., et al., Int J Cancer, doi: 10.1002/ijc.27436 (2012)). This impact on hematogenous dissemination is related to changes in blood vasculature characterized by pericyte detachment, vessel enlargement and destabilization (Chabottaux, V., et al., J Cell Mol Med 13, 4002-4013 (2009)). The cellular interaction of MT4-MMP which contributes to tumor aggressiveness was not known before.
The object of the present invention was to determine whether MT4-MMP could contribute to an outside-in signaling involved in tumor aggressiveness and to provide new pharmaceutical compositions for use in the treatment of cancer.